The arrival of French Huguenots in 1562 marked the first recorded visit of Reformed Christians to America. After 1600, many Presbyterians from Europe followed them, to escape persecution for their beliefs and to seek religious freedom. As their number increased, scattered groups formed into congregations. By 1709 the first presbytery was organized in Philadelphia, and in 1789 the first general assembly of the Presbyterian Church was convened.

Presbyterian denominations in the United States have split and parts have reunited several times. Currently the largest Presbyterian denomination is the Presbyterian Church (USA). It was formed in 1983 as a result of reunion between the Presbyterian Church in the U.S. (PCUS), the so-called “southern branch,” and the United Presbyterian Church in the U.S.A. (UPCUSA), the so-called “northern branch.”

The Presbyterian Church (USA) maintains a broad spectrum of relationships with churches and ecumenical agencies in Asia and the Pacific, Latin America, the Caribbean, Africa, and the Middle East. Shared personnel and programme resources are extended to partner churches for mission endeavours, including evangelism, self-development, medical, education, and justice ministries. The Presbyterian Church (USA) receives into its midst persons from other churches around the world who serve in mission to the USA. Increasing emphasis is being placed on partnership in mission which is based on the needs of both US and other churches, and a high priority has been placed on development of global perspectives which can inform the whole life of the church. Focused attention on global issues is also central to the well-established Presbyterian peacemaking and hunger programmes.

Domestically, special attention has been given to issues of evangelism, multiculturalism, racial and economic justice, and relationships of Christians with the peoples of Jewish and Muslim faiths. There is also attention to development of curricula resources that teach the Reformed tradition upon whose roots Presbyterians move out into fellowship in the wider community of churches. The general assembly has had a special theological task force on the peace, purity and unity of the church, whose charge is to "lead the Presbyterian Church (USA) in spiritual discernment of our Christian identity in and for the 21st century ... seeking the peace, purity and unity of the church." The church is served by ten theological seminaries and a school of Christian education.

Within the United States, the Presbyterian Church (USA) is active not only in the National Council of Churches but also in Churches Uniting in Christ. CUIC is successor to the former Consultation on Church Union and is a covenantal relationship with the African Methodist Episcopal Church, the African Methodist Episcopal Zion Church, the Christian Church/Disciples of Christ, the Christian Methodist Episcopal Church, the Episcopal Church, the International Council of Community Churches, the United Church of Christ and the United Methodist Church. In 1999, the Presbyterian Church (USA) entered a full communion relationship with the Evangelical Lutheran Church in America, the Reformed Church in America and the United Church of Christ.

Offices of the general assembly of the Presbyterian Church (USA), the highest governing body of the church, are located in Louisville, Kentucky. The Board of Pension of the general assembly and the Presbyterian Historical Society are both located in Philadelphia, Pennsylvania and the Presbyterian Foundation is located in Jeffersonville, Indiana.